Colesevelam hydrochloride: a specifically engineered bile acid sequestrant

Transcription

1 Future Lipidology ISSN: (Print) (Online) Journal homepage: Colesevelam hydrochloride: a specifically engineered bile acid sequestrant Padmini Manghat & Anthony Wierzbicki To cite this article: Padmini Manghat & Anthony Wierzbicki (2008) Colesevelam hydrochloride: a specifically engineered bile acid sequestrant, Future Lipidology, 3:3, To link to this article: Copyright 1994 Taylor and Francis Group LLC Published online: 18 Jan Submit your article to this journal Article views: 257 Full Terms & Conditions of access and use can be found at

2 DRUG EVALUATION Colesevelam hydrochloride: a specifically engineered bile acid sequestrant Padmini Manghat & Anthony S Wierzbicki Author for correspondence St Thomas Hospital, Department of Chemical Pathology, Lambeth Palace Road, London SE1 7EH, UK Tel.: ; Fax: ; anthony.wierzbicki@ kcl.ac.uk There is a well established association between serum cholesterol and coronary heart disease and this relationship has been found to be related to concentration and is continuous over the entire distribution of cholesterol levels. Recent studies have shown that intensive lipid lowering is beneficial and more stringent guidelines are advocated to improve the clinical outcome. Although statins are the first-line agents for the treatment of hypercholesterolemia, often it is evident that combination therapy is required to achieve the desired reduction in LDL-cholesterol (LDL-C). Niacin and bile acid sequestrants were among the first lipid-lowering drugs developed to lower LDL C and have been established to be effective in both monotherapy and combination therapy. However, tolerability and compliance issues have limited the use of the traditional bile acid sequestrants. Colesevelam hydrochloride is the newest bile acid sequestrant and shows reduced adverse effects, improved tolerance and better compliance. Keywords: bile acid sequestrant, cardiovascular, cholesterol, colesevelam HCl, diabetes part of Epidemiological studies and clinical trials have established dyslipidemia as a major independent risk factor for coronary artery disease (CAD). A reduction in LDL-cholesterol (LDL-C) levels has been shown to reduce coronary events and mortality in patients with and without previous CAD [1,2]. A meta-analysis of data from 90,056 individuals in 14 randomized trials of statin showed that statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation and stroke by approximately 20% per 1 mmol/l reduction of LDL-C, largely irrespective of lipid profile or other presenting characteristics (p < ) [3]. This was established in both primary and secondary prevention studies. Lower is better for LDL-C Intensive lipid lowering has also been shown to be beneficial in modifying the atherosclerotic process. The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) trial has demonstrated enhanced regression of carotid intima-media thickness (cimt) within 1 year in the setting of marked LDL-C reduction with atorvastatin 80 mg compared with the more modest LDL-C reduction achieved with pravastatin 40 mg (p = 0.03) [4]. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared the rate of CAD progression for patients treated with two different statins using coronary intravascular ultrasound [5]. This concluded that intensive treatment with of atorvastatin 80 mg in patients with moderate cholesterol elevations reduced progression of coronary atherosclerosis (p = 0.02) compared with a more moderate lipid-lowering regimen consisting of pravastatin 40 mg [6]. Intensive statin therapy has also demonstrated significant regression of atherosclerotic lesions in asymptomatic and secondary-prevention patients [7,8]. The A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) trial showed that a reduction of 53% in LDL-C by high-intensity statin therapy over 2 years in secondary-prevention patients led to a 6.8% median reduction of total atheroma volume compared with baseline. In this trial, a 15% increase in HDL-C also occurred. The regression was more related to LDL-C reduction rather than the dose of statin. Patients who reached an LDL-C below 2.6 mmol/l (100 mg/dl) showed a larger percent regression in plaque size compared with those that did not achieve this cholesterol goal. Statins are the primary therapy for elevated LDL-C. In patients not at target on monotherapy, end point evidence suggests a role of bile acid (BA) sequestrants (BASs), niacin or fibrates [9]. Bile acid sequestrants Bile acid sequestrants were among the first lipidlowering drugs demonstrated to reduce the risk of cardiovascular disease (CVD) [10]. Cholestyramine and colestipol have been used for a number of years, but tolerability and compliance issues have limited the use of these traditional BASs. Colesevelam hydrochloride (HCl) is a nonabsorbable / Future Medicine Ltd ISSN Future Lipidol. (2008) 3(3),

3 DRUG EVALUATION Manghat & Wierzbicki lipid-lowering agent that has been specifically designed to bind BAs with high affinity [11]. This drug was approved by the US FDA in May 2000 and was recently launched in the UK as well as other European countries for use alone or in combination with other lipid-lowering medications. This article reviews the mechanism of action, pharmacokinetics, pharmacodynamics, safety and efficacy of colesevelam HCl. Mechanism of action Bile acids are synthesized from hepatic cholesterol and stored in the gallbladder. During digestion, BAs are secreted into the small intestine, where they solubilize dietary fats and fatsoluble vitamins to facilitate their absorption and transport. Of the secreted BAs, 95% is reabsorbed from the distal ileum and transported back to the liver through the enterohepatic circulation, and the remaining 5% is excreted in feces [12]. Colesevelam HCl binds BAs in the intestine impeding their reabsorption. As the BA pool becomes depleted, the hepatic enzyme, cholesterol 7α-hydroxylase, is upregulated, which increases the conversion of cholesterol to BAs. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effects of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors [12]. These compensatory effects result in increased clearance of LDL-C, resulting in decreased serum LDL-C levels. Effects on VLDL production may increase triglyceride levels but HDL-C is generally unaffected or slightly increased [101]. Colesevelam HCl is a polyallylamine crosslinked with epichlorohydrin and alkylated with 1-bromodecane and 6-bromohexyl-trimethyl ammonium bromide [13]. Unlike the conventional BAS, the backbone of colesevelam HCl was specifically engineered to contain long hydrophobic side chains, which maximise hydrophobic interactions with BA, thus enhancing affinity, specificity and capacity compared with the conventional BAS (Figure 1) [13 15]. Colesevelam HCl binds BA via both hydrophobic interactions and ionic binding with primary amines, while quaternary amine side chains stabilize the structure [15]. Thus, a large number of BAs can bind to and remain bound by the colesevelam HCl polymer allowing for an increase in fecal excretion of BA per dose administered [12]. Colesevelam HCl binds to both dihydroxy and trihydroxy BA and has a greater affinity for trihydroxy BA than the traditional BAS [15]. The crosslinking with epichlorohydrin makes the polymer as innocuous as possible in the GI tract by both eliminating the possibility of systemic absorption and by reducing the negative interactions between the polymer and the lining of the GI tract [13]. Figure 1. Comparison of the molecular structure of the bile acid sequestrant cholestyramine and colesevelam HCl. Conventional bile acid sequestrant Colesevelam hydrochloride Polymer backbone Bound bile acid Amine-binding site Amine-binding site Hydrophobic side chains 238 Future Lipidol. (2008) 3(3)

4 Colesevelam hydrochloride DRUG EVALUATION Pharmacokinetics Colesevelam HCl is a water-absorbing hydrogel and is not absorbed from the GI tract. The evidence that colesevelam HCl is not absorbed comes from human and animal data indicating no significant urinary excretion and negligible tissue concentrations of the radiolabeled agent after single-dose administration and after repeated administration for 28 days [10]. The radiolabel was shown to be completely excreted within 48 h via the feces and no difference was observed between the dosage schedules [101]. Drug interactions Bile acid sequestrants have a tendency to interact with other substances in the GI tract, thereby altering the pharmacokinetics of the medicinal products. Studies on digoxin have clearly shown that cholestyramine impairs digoxin absorption producing a significant reduction of 32% in the area under the curve (AUC) of digoxin compared with digoxin alone [16]. The interaction of cholestyramine with warfarin and valproic acid was evaluated in separate studies and these have shown that cholestyramine reduced the AUC of warfarin by 25% and valproic acid by 16% [17,18]. However, colestipol was not found to interfere with the pharmacokinetics of warfarin [19]. Concurrent administration of cholestyramine or colestipol with propranolol has been shown to alter the pharmacokinetics of propranolol compared with the administration of propranolol alone [20]. The pharmacokinetics of colesevelam HCl coadministered with six drugs, namely quinidine, valproic acid, digoxin, warfarin, sustained-release verapamil and metoprolol, the drugs which are commonly used in the treatment of cardiovascular disease and have been shown to interact with the other BASs, were studied in six open-label, sequential-treatment studies involving 172 subjects who were not on any other prescription drugs except oral contraceptives (n = 19) and hormone-replacement therapy (HRT; n = 3) [21]. In this study, all the subjects received the potentially interacting drug with or without colesevelam HCl 4.5 g. The maximum dose of colesevelam HCl was used to maximize the probability of observing the effects of colesevelam HCl on absorption of the coadministered drug. The plasma levels of the coadministered drug were determined using validated analytical procedure. This study showed that colesevelam HCl did not alter plasma levels of valproic acid, warfarin, digoxin, quinidine or metoprolol appreciably, although verapamil plasma levels were somewhat decreased [21]. Colesevelam HCl was considered to have no significant effect on the bioavailability of these drugs if the 90% confidence intervals for the mean ratios (%) for log transformed maximal plasma concentration (C max ), AUC (0-t) and AUC (0 ) with and without colesevelam HCl was within the range of %. Table 1 shows that the bioavailability of all these drugs, with the exception of verapamil, are not affected by colesevelam HCl. The effects of colesevelam HCl on the pharmacokinetic profile of verapamil was found to be different from the other drugs tested. Coadministration of colesevelam HCl with sustained-release verapamil resulted in decreased peak plasma concentrations (-31%) and AUC (-11%) of verapamil, as compared with verapamil alone, although the AUC of the molar sum of verapamil and its metabolite norverapamil was only minimally decreased. There is a great deal of interindividual variability for verapamil in the absence of colesevelam HCl, and the C max and AUC increased 28- and 11-fold, respectively, among patients when the drug was administered alone [21]. Therefore, the clinical significance of the interaction of colesevelam HCl and verapamil is unknown. Although there was no significant alteration of warfarin drug levels with warfarin and colesevelam HCl coadministration, postmarketing experience has shown that concomitant Table 1. Mean ratios (%) for Ln (C max ), Ln [AUC (0-t) ] and Ln [AUC (0 ) ] of six drugs administered with and without colesevelam HCl. Plasma digoxin levels beyond 24 h were below the limit of sensitivity of the assay and, therefore, [AUC (0 ) ] could not be ascertained. Quinidine Valproic acid Digoxin Warfarin Verapamil Metoprolol Ln (C max ) Ln [AUC (0 t) ] Ln [AUC (0 ) ] AUC: Area under the curve; Ln: Natural logarithm. Taken from [21]

5 DRUG EVALUATION Manghat & Wierzbicki administration of colesevelam HCl reduced the international normalized ratio (INR) in patients receiving warfarin therapy [102] and, therefore, INR should be monitored frequently during initiation of colesevelam HCl therapy and then periodically thereafter in these patients. Postmarketing experience has also shown that concomitant administration of colesevelam HCl with phenytoin increased seizure activity or decreased phenytoin levels and, therefore, phenytoin should be administered at least 4 h prior to colesevelam HCl [102]. The evaluation of the effect of colesevelam HCl on the pharmacokinetics of lovastatin showed that coadministration of lovastatin 20 mg with colesevelam HCl 2.3 g did not have any influence on the bioavailability of lovastatin [22]. When lovastatin was administered 4 h later than colesevelam HCl, a statistically significant decrease was found in the C max (-63%) and AUC (0-t) (-37%) of lovastatin, and the increase in C max (+61%) and AUC (0-t) (+50%) of lovastatin hydroxy-acid. This change was most likely due to food interactions and time dependency of lovastatin rather than an interaction with colesevelam HCl [22]. However, the doses of both lovastatin and colesevelam HCl used in this study were low and this should be investigated further with maximum doses of both drugs. Colesevelam HCl, when coadministered with fenofibrate, did not affect the bioavailability of fenofibrate or affect the total drug exposure as measured by the AUC (0-t) and AUC (0- ) of fenofibrate. When administered 4 h following fenofibrate, there was no significant change in the bioavailability of fenofibrate [23]. A pilot study measured the total, unconjugated and conjugated levels of ezetimibe in patients on colesevelam HCl and ezetimibe combination therapy and ezetimibe alone [24]. A reduction of 19.5% in ezetimibe levels with concomitant colesevelam HCl treatment was observed. However, the reduction in ezetimibe levels with concomitant colesevelam HCl treatment was not statistically significant and was less than the 45% reduction seen with concomitant cholestyramine administration [25]. Thus, colesevelam HCl does not significantly affect the pharmacodynamics of ezetimibe. Enhanced LDL lowering has been established with colesevelam statin, colesevelam fenofibrate and colesevelam ezetimibe combinations, and this further confirms that colesevelam HCl does not interfere with the bioavailability of these coadministered lipid-lowering medications. Drugs such as glyburide, levothyroxine and oral contraceptives containing ethinyl estradiol and norethindrone have been shown to interact with colesevelam HCl and, therefore, should be administered at least 4 h prior to colesevelam HCl [102]. Bile acid sequestrants are known to reduce the bioavailability of some of the coadministered drugs due to the nonspecific binding of BAS to these drugs. Compared with conventional BASs, colesevelam HCl has greater affinity, and higher capacity for binding BAs due to its polymer structure engineered for greater BA sequestration [12]. Lower doses of colesevelam HCl (3.8 g) as compared with cholestyramine (16 g) has been shown to cause similar reductions in LDL-C and, therefore, under physiological conditions colesevelam HCl has more BAs bound per gram of polymer and relatively fewer binding sites available to interact with other drugs [21]. This could explain the minimal drug drug interactions seen with colesevelam HCl as compared with the traditional BASs [21]. Clinical data The efficacy, tolerability and safety of colesevelam HCl as monotherapy has been evaluated in two multicenter, randomized, double-blinded, placebo-controlled trials involving 149 and 494 patients with primary hypercholesterolemia over 6 and 24 weeks, respectively [26,27]. The percentage changes in lipid parameters compared with baseline for each treatment group in the 24-week trial is given in Table 2. LDL-C Both studies have shown that colesevelam HCl decreased LDL-C in a dose-dependent manner. In the 6-week trial, colesevelam HCl was administered at four dosages (1.5, 2.25, 3.0 or 3.75 g) and the two groups receiving the highest dosage showed a significant reduction of LDL-C from the baseline by 9 and 19%, respectively [26]. In the 24-week trial, patients were randomized to receive placebo or colesevelam HCl 2.3, 3.0, 3.8 or 4.5 g/day and a statistically significant reduction of LDL-C occurred with all the colesevelam HCl treatment groups when compared with the placebo group [27]. At the highest dose (4.5 g) colesevelam HCl produced an 18% mean and a 20% median reduction in LDL-C levels as compared with baseline values [27]. The greatest reduction in LDL-C was achieved in the first 2 weeks and sustained 240 Future Lipidol. (2008) 3(3)

6 Colesevelam hydrochloride DRUG EVALUATION Table 2. Percentage change in lipid parameters from baseline for patients treated with colesevelam HCl (24-week trial). Dose (g/day) Patients (n) Total cholesterol (mean) LDL-cholesterol (mean) Triglycerides (median) HDL-cholesterol (median) ApoB (mean) Placebo * Colesevelam HCl * -9* 9* 3* -6* 3* Colesevelam HCl * -12* 5* 4* -8* 3* Colesevelam HCl * -15* 10* 3* -12* 0 Colesevelam HCl * -18* 9* 3* -12* 2 *p < 0.05 relative to baseline. HCl: Hydrochloride. Taken from [27]. ApoA1 (mean) over the course of the study in both the trials. Both studies have shown that higher baseline LDL-C levels led to a greater absolute reduction in LDL-C. However, the percentage LDL-C reductions were less sensitive to baseline levels [27]. Total cholesterol The groups receiving the highest dosage of colesevelam HCl (3 and 3.75 g/day) in the 6-week trial group, and all the four treatment groups in the 24-weeks trial, showed significant reductions in total cholesterol relative to the baseline. The largest mean percent reduction was observed in the highest dosage group (10% for 4.5 g/day) in the 24-week study [27]. HDL-cholesterol & triglycerides HDL-C increased significantly by 11.2% (p = 0.006) and 8.1% (p = 0.02) in the two groups receiving the highest dosage of colesevelam HCl 3.0 and 3.75 g/day, respectively, in the 6-week trial, and in all the four treatment groups in the 24-week study with statistically significant percentage increases of 3 4% compared with baseline. Median triglyceride levels increased modestly from baseline to end point in the placebo group (5%) and all the colesevelam HCl treatment groups (5 10%; p < 0.05) [27]. However, increases in triglyceride levels in all the colesevelam HCl treatment groups were not significantly different to placebo [27]. Combination therapy The efficacy and safety of colesevelam HCl alone and in combination with HMG-CoA reductase inhibitors was evaluated in three randomized, multicenter, double-blind trials. With simvastatin A total of 258 adults with moderate hypercholesterolemia were randomly assigned to receive daily doses of placebo, colesevelam HCl 3.8 g, simvastatin 10 mg, colesevelam HCl 3.8 g with simvastatin 10 mg, colesevelam HCl 2.3 g, simvastatin 20 mg or colesevelam HCl 2.3 g with simvastatin 20 mg for 6 weeks [28]. Mean LDL-C levels decreased relative to baseline in the placebo group (p < 0.05) and in all active treatment groups (p < ). For groups treated with combination therapy, the mean reduction in LDL-C level was 42% (p < compared with baseline), which exceeded the reductions for simvastatin 10 mg (-26%) or 20 mg (-34%) alone, or for colesevelam HCl 2.3 g (-8%) or colesevelam HCl 3.8 g (-16%) alone (p 0.001) (Figure 2). The proportion of patients achieving LDL-C reductions below 40% increased from 9% for simvastatin 10 mg to 62% for colesevelam HCl 3.8 g/simvastatin 10 mg and from 28% for simvastatin 20 mg alone to 60% for colesevelam HCl 2.3 g/simvastatin 20 mg combination [28]. No patients treated with colesevelam HCl alone achieved a greater than 40% reduction in LDL-C. Mean total cholesterol decreased significantly in all treatment groups and the greatest reductions were seen with combination therapy, which were superior to either colesevelam HCl or simvastatin alone (p < 0.01) (Figure 2) [28]. The effects of combination therapy on serum HDL-C and triglyceride levels were similar to those for simvastatin alone, except for colesevelam HCl 3.8 g alone, which increased median triglyceride levels by 11% (Figure 2). This increase was similar to that seen with other BASs. Reductions in ApoB levels were observed in placebo and all treatment groups compared with baseline, and the decreases were significant 241

7 DRUG EVALUATION Manghat & Wierzbicki Figure 2. Percentage change in levels of total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides from baseline to end of treatment. Percentage change Total cholesterol LDL-C HDL-C TG , ,2 1, ,21, Placebo Simvastatin 20 mg/day Colesevelam 3.75 g/day + simvastatin 10 mg/day Simvastatin 10 mg/day Colesevelam 2.25 g/day + simvastatin 20 mg/day LDL-C and total cholesterol values are expressed as mean, whereas HDL-C and TG values are expressed as median. (A) p < 0.05 versus placebo. (B) p < 0.05 versus simvastatin 10 or 20 mg/day. HDL-C: HDL-cholesterol; LDL-C: LDL-cholesterol; TG: Triglyceride. Reprinted from [28] with permission from Elsevier. compared with the changes in the placebo group (p < 0.01) [28]. The decline in ApoB levels with both combination treatments were greater than those with colesevelam HCl or simvastatin alone (p < 0.05). ApoA1 levels increased in patients receiving colesevelam HCl 2.3 g, simvastatin 20 mg or combination therapies, and this was found to be greater than the changes in the placebo group (all p < 0.05) [28]. The percentage changes in lipid parameters compared with baseline with combination therapy is given in Table 3. With atorvastatin The efficacy and safety of coadministration of colesevelam HCl and atorvastatin was examined in a 4-week, randomized, multicenter, double-blind and placebo-controlled study involving 94 hypercholesterolemia patients [29]. Patients were randomized among five groups: placebo; colesevelam HCl 3.8 g/day, atorvastatin 10 mg/day, coadministered colesevelam HCl 3.8 g/day plus atorvastatin 10 mg/day or atorvastatin 20 mg/day. LDL-C was reduced significantly by 12 53% in all active treatment groups (p < 0.01). LDL-C reductions with combination therapy (48%) were found to be statistically superior to colesevelam HCl (12%) or low-dose atorvastatin (38%) alone (p < 0.01), but similar to those achieved with atorvastatin 80 mg/day (53%) [29]. A greater than 40% reduction in LDL-C occurred in 85% of patients taking atorvastatin 80 mg/day as compared with 72% of patients taking the combination therapy and 39% taking atorvastatin 10 mg/day [29]. Total cholesterol decreased 6 39% in all active treatment groups (p < 0.05) and HDL-C increased 4 11% in all groups, including the placebo group (p < 0.05), and the maximum increase occurred in the colesevelam atorvastatin group. Triglycerides were significantly reduced in patients taking atorvastatin alone (p < 0.05), and were unaffected by combination therapy [29]. Colesevelam HCl alone increased triglycerides by 10%, which was not significantly different from the placebo group. ApoB levels decreased 10 46% in all active treatment groups relative to baseline (p < 0.01), mirroring the reductions in LDL-C, and the reduction in the combination-therapy group was 38%. ApoA1 increased significantly relative to baseline in patients taking colesevelam HCl alone (p < 0.05) or colesevelam HCl combined with atorvastatin (p < 0.001) by 4 and 9%, respectively. No significant changes in ApoA1 were observed in the patients treated with lowor high-dose atorvastatin alone [29]. The 242 Future Lipidol. (2008) 3(3)

8 Colesevelam hydrochloride DRUG EVALUATION Table 3. Colesevelam HCl in combination with HMG-CoA reductase inhibitors and ezetimibe: percentage change in lipid parameters from baseline. Combination Duration of treatment (weeks) Treatment Patients (n) Total cholesterol LDL-C Triglycerides HDL-C ApoB ApoA1 Ref. With simvastatin 6 Placebo [28] Colesevelam HCl ± 9* -42 ± 11* * -33 ± 11* 10 ± 10* 3.8 g + simvastatin 10 mg Colesevelam HCl ± 10* -42 ± 13 * -12* 4* -32 ± 12* 10 ± 12* 2.3 g + simvastatin 20 mg With atorvastatin 4 Placebo [29] Colesevelam HCl ± 2* -48 ± 3* -1 11* -38 ± 2* 9 ± 2* 3.8 g + atorvastatin 10 mg With lovastatin 4 Placebo [30] Colesevelam HCl 27-21± 1* -34 ±1* 9 ± 7 3 ± 2-24 ± 10* 5 ± 9* 2.3 g + lovastatin 10 mg (both dosed together) Colesevelam HCl ± 2* -32 ± 3* -3 ± 4 3 ± 2-24 ± 10* 4 ±9 2.3 g + lovastatin 10 mg (both dosed apart) With ezetimibe 12 Placebo [24] Colesevelam HCl 9-15 ± 8-30 ± ± 85 5 ± ± g twice-daily + ezetimibe 10 mg/day With ezetimibe 6 Placebo [24] Colesevelam HCl -20* -32* * 6.7* 3.8 g/day + ezetimibe 10 mg LDL-C, total cholesterol and ApoB are mean ± standard deviation (SD) values. HDL-C and triglyceride are median values in simvastatin and atorvastatin groups and mean ± SD values in the ezetimibe and lovastatin groups. ApoA1 values are not available for the ezetimibe combination therapy group. *p < 0.05 for comparison of baseline with end point. HDL-C: HDL-cholesterol; LDL-C: LDL-cholesterol

9 DRUG EVALUATION Manghat & Wierzbicki percentage changes in lipid parameters compared with the baseline for combination therapy is given in Table 3. With lovastatin Colesevelam HCl alone and in combination with lovastatin was studied in a 4-week, randomized, multicenter, double-blind and placebocontrolled study involving 135 patients with moderate hypercholesterolemia [30]. Patients were randomly assigned to 4 weeks of daily treatment with placebo, colesevelam HCl 2.3 g/day, lovastatin 10 mg/day, colesevelam HCl 2.3 g plus lovastatin 10 mg dosed together or colesevelam HCl 2.3 g plus lovastatin 10 mg dosed apart. The combination of colesevelam HCl and lovastatin dosed together and apart resulted in a statistically significant greater reduction in LDL-C and total cholesterol than either drug alone (p < 0.05). Mean HDL-C and triglyceride concentrations increased significantly in the colesevelam HCl alone group (p < 0.01 and p < , respectively). The median triglyceride and HDL-C levels were used in the other two studies as compared with mean values in this study. Median triglycerides and HDL-C levels were used because these are not normally distributed in the population and the median value is a more robust measurement. Both ApoB and ApoA1 decreased significantly from the baseline values in all active-treatment groups, except the colesevelam HCl 2.3 g group. Varied dosing intervals in the combination groups gave similar changes in LDL-C and total cholesterol, demonstrating that colesevelam HCl does not interfere with the pharmacokinetics of lovastatin [30]. The percentage changes in lipid parameters compared with the baseline for combination therapy with lovastatin dosed both together and apart is given in Table 3. With stable statin therapy The efficacy of adding colesevelam HCl to stable simvastatin, atorvastatin or pravastatin treatment was investigated in three randomized, double-blind, placebo-controlled, parallel 6-week trials involving 204 patients with primary hypercholesterolemia that looked at the effects of colesevelam HCl on C-reactive protein (CRP) [31]. A pooled analysis showed that adding colesevelam HCl to statin therapy significantly reduced LDL-C levels by 16% when compared with baseline (p = ) and 9% when compared with placebo (p = ) [31]. Four-times as many patients administered colesevelam HCl achieved a LDL-C target level of less than 2.6 mmol/l (100 mg/dl) compared with patients administered placebo (p < ) [31]. Colesevelam HCl plus statins also significantly lowered total cholesterol levels from baseline (p < 0.05), and this was more than the placebo plus statin values. Triglycerides and ApoA1 increased significantly in the colesevelam HCl plus statin group compared with the placebo plus statin group. However HDL-C and ApoB levels showed no significant changes [31]. Combination trials have shown that the addition of colesevelam HCl to statin therapy is well tolerated and was more efficacious than using the individual drugs alone. However combination therapy with higher doses (e.g., 40 or 80 mg) of simvastatin and with other statins such as pravastatin, fluvastatin and rosuvastatin has not been evaluated. With ezetimibe Two studies evaluated the combination of colesevelam HCl and ezetimibe [24,32]. They showed that there were no significant pharmacodynamic or pharmacokinetic interactions of colesevelam HCl with ezetimibe. This is in contrast to cholestyramine, which, when coadministered with ezetimibe, was found to reduce the bioavailability of ezetimibe since cholestyramine binds ezetimibe and reduces the absorption [33]. There were no differences between the groups in terms of baseline lipid levels in both the studies. Zema et al. assessed the efficacy and safety of colesevelam HCl and ezetimibe alone and in combination in 12 patients with hypercholesterolemia who had refused, or were intolerant of, statin therapy [32]. This was an open-label, crossover design study and the patients were randomized to receive either oral colesevelam HCl g twice-daily (3.8 g/day) or ezetimibe 10 mg/day. After completion of 6 weeks of monotherapy, the alternative agent was added and the patient maintained on combination therapy for an additional 6 weeks. Combination therapy with colesevelam HCl/ezetimibe resulted in an additional reduction in LDL-C and non-hdl-c levels of approximately 20% (p < 0.005) and 16% (p < 0.01), respectively, compared with monotherapy with either agent [32]. The second study was a double-blind, randomized, parallel-design study involving 20 patients with hypercholesterolemia [24]. The subjects were allocated to baseline ezetimibe 244 Future Lipidol. (2008) 3(3)

10 Colesevelam hydrochloride DRUG EVALUATION 10 mg/day and randomized to either placebo or colesevelam HCl g twice-daily. The percentage reduction in LDL-C at 12 weeks in the combination therapy group (30%) was borderline greater than the ezetimibe alone group (24%) and was not found to be significant (p = 0.102) (Table 3). A recent multicenter, randomized, doubleblind, placebo-controlled, parallel-group study involving 86 patients with primary hypercholesterolemia compared the effect of colesevelam HCl in combination with ezetimibe to ezetimibe monotherapy [34]. The subjects who participated in this study received colesevelam HCl 3.8 g/day plus ezetimibe 10 mg/day or placebo plus ezetimibe 10 mg/day for 6 weeks. This large study showed that the combination therapy produced a mean percentage change in LDL-C of -32% versus -21% with ezetimibe monotherapy (p < ). Combination therapy was significantly more effective than ezetimibe alone at producing mean percentage reductions in total cholesterol (-20%), non-hdl-c (-26.7%) and ApoB (-22.7%), and increases in ApoA1 (+6.7%; p < for all). No significant change in median triglyceride levels was seen in both the groups. A retrospective chart review study was performed of 40 patients in whom ezetimibe 10 mg/day was added to a stable regimen that included a BAS and 33 patients were on colesevelam HCl (average daily dose g) [35]. This study showed that ezetimibe lowered total cholesterol by 18% and LDL-C by 19% (p < 0.03) when added to a stable lipid-lowering regimen that included colesevelam HCl [35]. Taken together, the results indicate that additional LDL-C lowering could be attained with the addition of colesevelam HCl to ezetimibe treatment. With fenofibrate The amount of LDL-C reduction achieved by adding the specifically engineered BAS colesevelam HCl to a stable dose of fenofibrate in patients with mixed hyperlipidemia was evaluated in a randomized, double-blind, placebo-controlled, parallel-group study. In this study, 129 patients received fenofibrate 160 mg/day for 8 weeks and were then randomized to receive colesevelam HCl 3.75 g/day or placebo in addition to fenofibrate 160 mg/day for 6 weeks [36]. Fenofibrate plus colesevelam HCl produced a mean percentage change in LDL-C of -10.4% versus +2.3% with fenofibrate monotherapy (p < ) and the combination therapy was significantly more effective than fenofibrate alone at reducing levels of non-hdl-c, total cholesterol and ApoB (p ). Colesevelam HCl did not significantly affect the triglyceride-lowering or HDL-C-raising effects of fenofibrate. Both treatment regimens were safe and well tolerated [36]. Effects of colesevelam HCl on other cardiovascular risk factors C-reactive protein Elevated levels of C-reactive protein (CRP), a biomarker of inflammation, are associated with an increased risk of coronary heart disease (CHD). Two randomized, double-blind, placebo-controlled trials examined the effects of colesevelam HCL on high sensitivity (hs)-crp [31,36]. In one study, colesevelam HCl was used as monotherapy and in the other colesevelam HCl was added to statins in patients with hypercholesterolemia. Both studies demonstrated that colesevelam HCl significantly lowered hs-crp. No correlation was found between LDL-C lowering and hs-crp lowering (r = 0.3) [37]. One study recruited 60 patients and randomly assigned patients to one of the two study arms: colesevelam g/day HCl or placebo for 6weeks [37]. Colesevelam HCl therapy for 6 weeks resulted in significant 15.9 and 18.7% reductions in median CRP levels compared with baseline and placebo, respectively (p < 0.025). There were no significant differences in other inflammatory markers such as plasma IL-6 or TNF-α before and after therapy [37]. The other study which examined the effects of colesevelam HCl on LDL-C when added to statin therapy in patients with hypercholesterolemia also looked at the effects on hs-crp [31]. This study demonstrated that that the change in hs-crp levels with colesevelam HCl added to statins was significant compared with the change in hs-crp when placebo was added to stable statin therapy in patients with primary hypercholesterolemia, and the treatment difference between the two groups in terms of percentage reduction in median hs-crp was 23.3% (p < 0.01) [31]. Given the favorable effects on LDL-C and CRP levels found in this study, the addition of colesevelam HCl to a statin may provide additional CVD risk reduction over the same dose of statin used as monotherapy

11 DRUG EVALUATION Manghat & Wierzbicki LDL particle number When LDL particles are compositionally abnormal, due to decreased core cholesterol content, LDL-C concentration underestimates the number of LDL particles [38]. Increased LDL particle numbers measured by nuclear magnetic resonance (NMR) spectroscopy are stronger predictors of cardiovascular events than direct LDL-C measurement [38 40]. The effect of colesevelam HCl on LDL particle size and number measured by NMR spectroscopy was investigated in a multicenter, double-blind, placebocontrolled study involving 149 patients with moderate hypercholesterolemia who completed a dose-ranging trial with colesevelam HCl [41]. Mean LDL particle size increased only with colesevelam HCl 3.75 g/day (p = 0.01). Mean LDL particle number was reduced by 6.8% (p = 0.03) and 13.7% (p = ) in the colesevelam HCl 3.0 and 3.75 g/day treatment groups, respectively [41]. These changes were not influenced by baseline fasting triglyceride level or LDL particle size. Particle number reduction parallels reductions in ApoB and is likely to hint at the potential benefit of colesevelam HCl therapy. Increases in particle size have varying associations with cardiovascular disease since increased size of small dense particles is beneficial while very large particles may be atherogenic [42]. Colesevelam HCl is likely to have complex effects on particle sizes given that it raises triglycerides while also reducing ApoB. Statins have a larger effect on particle number than colesevelam HCl; however, the magnitude of reduction has been shown to be dependent on baseline LDL particle size. Type 2 diabetes A 24-week study on the lipid effects of colesevelam HCl in subjects with Type 2 diabetes showed a decrease in blood glucose levels [43], and this led to the Glucose Lowering Effects of Welchol Study (GLOWS), a randomized, double-blind, placebo-controlled pilot study to evaluate the effects of colesevelam HCl on glycemic control in subjects with Type 2 diabetes [44]. In this study, 65 subjects with Type 2 diabetes on oral antihyperglycemic medication (sulfonylurea and/or metformin) and a hemoglobin (Hb)A 1c value between 7.0 and 10%, were randomized to receive colesevelam HCl 3.7 g/day or matching placebo for 12 weeks. Compared with placebo, colesevelam HCl treatment was associated with a significant reduction in HbA1c at the end of treatment. The difference in least squares (LS) mean change in HbA1c between the colesevelam HCl and placebo groups was -0.5% (p = 0.007). In subjects with an HbA 1c 8.0% or greater at baseline and in subjects with an HbA 1C below 8% at baseline, the treatment difference in LS mean change in HbA 1c was -1.0% (p = 0.002) and -0.2%, respectively [44]. The difference in LS mean change in HbA 1c between treatment groups was similar among subjects taking a sulfonylurea alone, taking metformin alone and in subjects taking a sulfonylurea and metformin. In the colesevelam HCl group, fasting plasma glucose was decreased from baseline at 4 weeks and continued to decrease up to 8 weeks, but approached baseline levels by week 12; the reason for this pattern is unclear. Compared with placebo, colesevelam HCl treatment was associated with a significant reduction in postprandial glucose and fructosamine; the difference in LS mean change between groups at 12 weeks were mg/dl (1.7 mmol/l; p = 0.026) and -29 µmol/l (p = 0.011), respectively [44]. Compared with placebo, colesevelam HCl treatment significantly reduced mean LDL-C by 11.7% (p = 0.007), total cholesterol by 7.3% (p = 0.019) and ApoB by 11.8% (p = 0.003). There was no significant change in HDL-C or median triglyceride levels in the colesevelam HCl group compared with placebo. The mechanism by which colesevelam HCl affects glycemic parameters are not fully understood. Proposed mechanisms include a reduction in glucose absorption or changes in the time course of glucose absorption in the GI tract, disruption of the enterohepatic pathway of bile metabolism [44], or deactivation of farnesoid X receptor (FXR), a BA-activated nuclear receptor that plays a major role in the metabolism of BAs, cholesterol and glucose [45,46]. Its effects on lipids are partially mediated by increasing expression of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) by FXR-dependent and -independent pathways [47], and maybe by specific actions via the liver X receptor (LXR) on sterol regulatory element-binding protein (SREBP)-2 [48]. The limitations of the GLOWS study were that the population size was necessarily small and the study was of short duration and had a greater proportion of non-white subjects than the placebo group. This prompted the design of three double-blind, placebo-controlled, Phase III, add-on therapy trials involving 1018 patients to evaluate the use of colesevelam HCl as adjuvant therapy to improve glycemic control in patients with Type 2 diabetes who are inadequately controlled with commonly 246 Future Lipidol. (2008) 3(3)

12 Colesevelam hydrochloride DRUG EVALUATION prescribed oral hypoglycemic agents or insulin. This confirmed that colesevelam HCl significantly improved both lipid levels and HbA 1c in patients with Type 2 diabetes treated with a variety of glucose-lowering agents [32]; the findings are summarized in Table 4 [102]. Safety & tolerability Treatment-emergent adverse events that occurred in greater than 2% of patients in an integrated safety analysis are given in Figure 3 [26,101]. All doses of colesevelam HCl were reported to be well tolerated and had a reduced constipating side effect, which is typical of BASs [26,27]. There was no statistically significant difference across treatment groups and the placebo group, in the number of patients who experienced adverse events caused by colesevelam HCl treatment following monotherapy with different dosage levels of colesevelam HCl (placebo 41%, colesevelam HCl 1.5 g/day 40%, colesevelam HCl 2.25 g/day 53%, colesevelam HCl 3.0 g/day 52%, and colesevelam HCl 3.75 g/day 55%) [26]. The most common side effects were those that occurred in the body as a whole, such as infection. The second most frequent were those of the GI tract; flatulence and constipation being the most common complaints. There were no significant differences among treatment groups for the incidence of gastrointestinal adverse events [26,27] except for diarrhea reported by three out of 30 patients in the colesevelam HCl 2.25 g/day group. A minority of patients (2.7 10%) left the studies because of adverse events and no significant differences occurred between the groups in the frequency of withdrawal due to adverse events [26,27]. The overall compliance in the colesevelam HCl group was 93% in the 6-week study and 88 91% in the 6-month study and did not significantly differ from the placebo group (92%). Owing to the constipating effects, colesevelam HCl is not recommended in patients at risk of bowel obstruction [102]. No clinically significant changes were reported in serum chemistry values, hematology variables, iron status, vitamin or coagulation variables, with the exception of a non-dose-related alkaline phosphatase response (p = 0.01 and p < for the 1.5 and 3.0 g/day groups, respectively) [26]. In the group receiving the highest dosage (3.75 g/day) alanine transaminase (ALT; p < 0.001) and aspartate transaminase (AST; p = 0.02) were elevated from baseline levels, but remained within the normal range. Table 4. Effects of colesevelam HCl on lipid and glycemic parameters in patients with Type 2 diabetes mellitus treated with a variety of glucose-lowering agents. Clinical trial Clinical trial 1: colesevelam HCl 3.75 g/day or placebo add-on combination therapy with metformin ± OAD (n = 316) Clinical trial 2: colesevelam HCl 3.75 g/day or placebo add-on combination therapy with sulfonylurea ± OAD (n = 460) Clinical trial 3: colesevelam HCl 3.75 g/day or placebo add-on combination therapy with insulin ± OAD (n = 287) Duration (weeks) Percentage change in lipid parameters 26 TC: -4* LDL-C: -12* ApoB: -4* HDL-Cl: +1 Non-HDL-C: -6* TG: TC: -5* LDL-C: -16* ApoB: -6* HDL-C: +1 Non-HDL-C: -6* TG: +20* 16 TC: -3 LDL-C: -12* ApoB: -4 HDL-C: -1 Non-HDL-C: -3 TG: +23* Baseline HbA 1c (%) Treatment difference in glycemic parameters (p-value) 8.1 HbA 1c : -0.5% (p < 0.001) FPG (mean): -14 mg/dl (p = 0.01) 8.2 HbA 1c : -0.5% (p < 0.001) FPG (mean): -14 mg/dl (p = 0.009) 8.3 HbA 1c : -0.5 % (p < 0.001) FPG (mean): -15 mg/dl (p = 0.08) *p < for lipid parameters compared with placebo. FPG: Fasting plasma glucose; HbA 1C : Hemoglobin A 1C ; HDL-C: HDL-cholesterol; LDL-C: LDL-cholesterol; OAD: Oral antidiabetic drugs; TC: Total cholesterol; TG: Triglycerides. Taken from [102]

13 DRUG EVALUATION Manghat & Wierzbicki Figure 3. Adverse events that occurred in more than 2% of patients in an integrated safety analysis. Percentage of patients Placebo (n = 258) Colesevelam HCl (n = 807) 0 Headache Back pain Flatulence Constipation/ Diarrhea Adverse event Nausea Dyspepsia Myalgia Adapted from [102]. In combination with a HMG-CoA reductase inhibitor, constipation was reported by a slightly higher percentage of patients in the colesevelam/hmg-coa reductase inhibitor treatment group (10.3%) compared with the HMG-CoA only group (7.9%) (Figure 4) [28 30]. Compared with placebo, the percentage of patients reporting these adverse events were increased by approximately 5%. The gastrointestinal side effects do not appear to be markedly dose related, and increasing the dose to 4.5 g/day appears to be acceptable with regard to such adverse events. Myalgia was more frequent in patients in the colesevelam/hmg-coa reductase inhibitor treatment group (6.2%) and the HMG-CoA reductase only group (3.6%) compared with the colesevelam HCl only group (2.1%) (Figure 4) and the placebo group (0.4%) [28 30]. However, the difference in the incidence of myalgia between the colesevelam/hmg-coa reductase-inhibitor treatment group (6.2%) and the HMG-CoA reductase inhibitor only group (3.6%) was not statistically significant (p = 0.29). Colesevelam HCl used in combination with HMG-CoA reductase inhibitors did not alter the magnitude of the increases in liver function tests observed with the HMG-CoA reductase inhibitor. A total of 1.9% of placebo patients, 1.4% of colesevelam HCl alone group and 0.7% of both colesevelam/hmg-coa reductase inhibitor and HMG-CoA reductase inhibitor only patients experienced serious adverse events, and these levels were similar to what could be expected in a general population over the treatment period (Figure 4) [101]. Studies on the effects and tolerability of colesevelam HCl, a BAS and ezetimibe, which inhibits cholesterol absorption in the small intestine, have shown that the combination therapy did not significantly increase ALT levels or creatine kinase (CK) levels compared with colesevelam HCl monotherapy and was well tolerated [24,32,49]. Combination therapy with fenofibrate was also reported to be safe and well tolerated [36]. Therefore, combination of colesevelam HCl with a statin, ezetimibe or fenofibrate has no greater risk for adverse effects than any of the drugs administered alone. Bile acids are required for the absorption of the fat-soluble vitamins A, D, E and K. Therefore, colesevelam HCl could interfere with the absorption of these vitamins by an effect secondary to BA sequestration and lead to depletion of these vitamins, particularly vitamins E and K. Animal studies have demonstrated that while short-time exposure was well tolerated, chronic exposure required the supplementation of fat soluble vitamins in order to avoid vitamin depletion [101]. Among the patients treated with colesevelam HCl during the entire clinical development program of colesevelam HCl, vitamin K status was indirectly 248 Future Lipidol. (2008) 3(3)

14 Colesevelam hydrochloride DRUG EVALUATION assessed by measuring prothrombin time (PT) and partial thromboplastin time (PTT). The baseline and end point means were within the normal ranges and the magnitude of the changes were relatively small. However anemia and hemorrhages associated with vitamin K depletion have been observed in nonclinical studies in rats and dogs at doses that are 40-fold and eightfold, respectively, greater than the maximum recommended human dose. Owing to this finding, there is a potential safety concern in humans through interference with the absorption of fat-soluble vitamins and vitamin supplementation may be considered in patients on long-term treatment particularly in children as recommended in the NICE guidelines for familial hypercholesterolemia. Triglyceride elevations to 6 mmol/l or greater and 4 mmol/l or greater were seen in 2 and 7%, respectively, of patients on colesevelam HCl monotherapy. Increased hepatic cholesterol synthesis would probably increase the VLDL production and might explain the high triglycerides seen in some patients. However combination therapy with an HMG-CoA reductase inhibitor has shown that triglycerides were not increased due to the triglyceride lowering effects of Figure 4. Adverse events on combination therapy with HMG-CoA reductase inhibitors. Percentage of patients Adapted from [101]. Constipation/ Diarrhea Myalgia Adverse event HMG-CoA reductase inhibitor only Colesevelam/HMG-CoA reductase inhibitor Serious adverse events HMG-CoA reductase inhibitors [101]. The safety and efficacy of this drug, however, has not been established for patients with triglycerides higher than 3.4 mmol/l since such patients were excluded from the study. Therefore, colesevelam HCl should be used with caution in patients who have triglycerides higher than this level [103]. This may be significant in dyslipidemia associated with diabetes, characterized by increased levels of VLDL and triglycerides. In clinical trials in patients with Type 2 diabetes, colesevelam add-on combination therapy has been shown to increase triglyceride levels, and a significant increase occurred when colesevelam HCl was used in combination with sulfonylurea (median increase 18% compared with placebo) and with insulin (median increase 22% compared with placebo).therefore, lipid parameters, including triglyceride levels, should be obtained before commencing colesevelam HCl and periodically thereafter. The drug should be discontinued if triglycerides exceed 500 mg/dl (5.95 mmol/l) or if the patient develops hypertriglyceridemia-induced pancreatitis [102]. Dosage & administration Colesevelam HCl is available as a 625 mg tablet formulation [102,103]. Colesevelam HCl coadministered with an HMG-CoA reductase inhibitor is indicated as adjunctive therapy to diet to provide an additive reduction in LDL-C levels in patients with primary hypercholesterolemia who are not adequately controlled with a statin alone. Colesevelam HCl as monotherapy is indicated as adjunctive therapy to diet for reduction of elevated total and LDL-C in patients with isolated primary hypercholesterolemia, in whom a statin is considered inappropriate or is not well tolerated. As monotherapy, the recommended starting dose of colesevelam HCl is three tablets taken twice-daily with meals or six tablets oncedaily with a meal. For combination therapy, the recommended dose of colesevelam HCl is four to six tablets. For maximal therapeutic effect in combination with statins, the recommended dose is three tablets taken twice-daily with meals or six tablets taken once-daily with a meal. Colesevelam HCl can be dosed at the same time as the chosen HMG-CoA reductase inhibitor or the two medicinal products can be dosed apart [102,103]. Since food intake may increase the release of BAs, administration with meals and liquid is advised. In vitro studies have shown that the binding characteristics of colesevelam HCl 249